Expression und Funktion der Toll-Like Rezeptoren TLR-4 und TLR-9 an Zelllinien des Harnblasenkarzinoms

Das Harnblasenkarzinom ist eine der häufigsten malignen Tumorerkrankungen weltweit. 75%-85% der Patienten werden noch in nicht-muskelinvasiven Stadien diagnostiziert. Für einen Teil dieser Patienten stellt die Dispositionsprophylaxe mittels BCG-Instillation nach TUR eine effektive Therapie dar und wird empfohlen. Bis heute ist der Wirkungsmechanismus von BCG nicht vollständig geklärt, aber es ist bekannt, dass Bestandteile von BCG mit Toll-like Rezeptoren, unter ihnen TLR-4 und TLR-9, interagieren und dass CpG-ODN, ein TLR-9-Agonist, in vitro und in Tierversuchen dem BCG sogar überlegen ist. Trotzdem gibt es bisher nur wenige Untersuchungen zur Existenz und Funktionalität von Toll-like Rezeptoren auf Harnblasenkarzinomzellen selbst. Ziel dieser Arbeit war es daher, die Expression von TLR-4 und TLR-9 an verschiedenen Zelllinien des Harnblasenkarzinoms zu untersuchen und zu überprüfen, ob eine Stimulation dieser Rezeptoren durch ihren spezifischen Liganden zu Veränderungen im Zytokinexperssionsmuster, in der Zellproliferation und in der Zellinvasion führt. Alle untersuchten Harnblasenkarzinomzelllinien exprimierten TLR-9 mRNA und zumeist auch TLR-4 mRNA. Exemplarisch wurden für alle weiteren Untersuchungen vier Zelllinien gewählt. An ihnen wurde zunächst die TLR-4- und TLR-9- Proteinexpression mittels Immunzytologie bzw. Western Blot untersucht. Diese zeigte übereinstimmende Ergebnisse mit der mRNA-Expression. Zur Untersuchung der LPS-Effekte wurden T24 als Zelllinie mit starker TLR-4- Expression und BFTC als Zelllinie ohne TLR-4-Expression gewählt. LPS induziert eine signifikante IL-6- und TNFα-Antwort in der Zelllinie T24, nicht aber in BFTC. LPS hatte keinen Einfluss auf die Zellproliferation. Zur Untersuchung der CpG-ODN-Effekte wurden UMUC3 als Zelllinie mit starker TLR-9-Expression und RT112 als Zelllinie mit schwacher TLR-9-Expression gewählt. Es konnte gezeigt werden, dass INTERFERin® die Aufnahme von CpG-ODN in das Zellinnere, also den Ort der TLR-9-Expression, verstärkt. Daher wurde teilweise mit INTERFERin® gearbeitet, um minimale CpG-ODN-Effekte besser charakterisieren zu können. In der Zelllinie UMUC3 verstärkte CpG-A + INTERFERin® die Expression von IL-8, TNFα, INFß, VEGF-A und PlGF signifikant. CpG-B + INTERFERin® verstärkte nur die Expression von IL-8 und INFß. In der Zelllinie RT112 hatte CpG-A + INTERFERin® hingegen keine Effekte. CpG-B + INTERFERin® verstärkte die IL-8- und TNFα-Expression signifikant. Die Zellproliferation der Zelllinie UMUC3 wurde sowohl durch CpG-B alleine, als auch durch CpG-B + INTERFERin®, sowie durch CpG-A +INTERFERin® signifikant vermindert. Die Zellproliferation der Zelllinie RT112 wurde durch CpG-B und durch CpG-B + INTERFERin® signifikant vermindert. Beide CpG-Motive verstärkten in beiden Zelllinien die Zellinvasion signifikant, CpG-B hatte hierbei einen noch ausgeprägteren Effekt, als CpG-A. Dies zeigt, dass BCG und potentiell zukünftige Immunotherapeutika des nicht-muskelinvasiven Harnblasenkarzinoms, die ihre Wirkung über Toll-like Rezeptoren entfalten, immer auch Einfluss auf die Tumorzellen direkt nehmen, da diese selbst auch funktionelle Toll-like Rezeptoren exprimieren. Die Untersuchungen zu Zytokinexpression, Zellproliferation und Invasion verdeutlichen, dass dies, therapeutisch gesehen, sowohl positive, als aber auch negative Folgen haben kann. Diese Mechanismen und vor allem ihre Signalwege sollten noch genauer untersucht werden, um die Wirkung von Immunotherapeutika zu optimieren und einen Therapieerfolg vorhersehbarer zu machen

Enhancing Prostate Cancer Detection Accuracy in Magnetic Resonance Imaging–targeted Prostate Biopsy:Optimizing the Number of Cores Taken

Background and objective: The shift toward targeted biopsy (TBx) aims at enhancing prostate cancer (PCa) detection while reducing overdiagnosis of clinically insignificant disease. Despite the improved ability of TBx in identifying clinically significant PCa (csPCa), the optimal number and location of targeted cores remain unclear. This review aims to assess the optimal number of prostate biopsy magnetic resonance imaging (MRI)-targeted cores to detect csPCa. Methods: A narrative literature search was conducted using PubMed, focusing on studies published between January 2014 and January 2024, addressing factors influencing targeted core numbers during prostate biopsy. The search included both retrospective and prospective studies, prioritizing those with substantial sample sizes and employing terms such as “prostate biopsy”, “mpMRI”, “core number”, and “cancer detection”. Key findings and limitations: Two biopsy cores identified csPCa in 55–65% of cases. This detection rate improved to approximately 90% when the number of cores was ≥5. The inclusion of perilesional and systematic biopsies could maximize the detection of csPCa (from 10% to 45%), especially in patients under active surveillance or with prior negative biopsy results, although there is an increase in the overdiagnosis of indolent tumors (from 4% to 20%). Transperineal software-assisted target prostate biopsy may enhance cancer detection, particularly for tumors located at the apex/anterior part of the prostate. Increasing the number of TBx cores may incrementally raise the risk of complications (by 2–14% with each added core) and result in severe pain and significant discomfort for up to 17% and 25% of TBx patients, respectively. However, the overall rate and severity of these complications remain within acceptable limits. Conclusions and clinical implications: The optimal number of cores for targeted prostate biopsies should balance minimizing sampling errors with effective cancer detection and should be tailored to each patient's unique prostate characteristics. Up to five cores per MRI target may be considered to enhance the detection of csPCa, with adjustments based on factors such as prostate and lesion volume, Prostate Imaging Reporting and Data System, biopsy techniques, complications, patient discomfort, and anxiety. Patient summary: In this report, we found that increasing the number of biopsy cores up to ≥5 improves the detection rates of significant prostate cancer significantly to around 90%. Although inclusion of nearby and systematic biopsies enhances detection, increasing the biopsy count may lead to higher risks of complications and indolent tumors. A customized biopsy approach based on multiple variables could be helpful in determining the appropriate number of targeted biopsies on a case-by-case basis.</p

Enhancing Prostate Cancer Detection Accuracy in Magnetic Resonance Imaging–targeted Prostate Biopsy:Optimizing the Number of Cores Taken

Background and objective: The shift toward targeted biopsy (TBx) aims at enhancing prostate cancer (PCa) detection while reducing overdiagnosis of clinically insignificant disease. Despite the improved ability of TBx in identifying clinically significant PCa (csPCa), the optimal number and location of targeted cores remain unclear. This review aims to assess the optimal number of prostate biopsy magnetic resonance imaging (MRI)-targeted cores to detect csPCa. Methods: A narrative literature search was conducted using PubMed, focusing on studies published between January 2014 and January 2024, addressing factors influencing targeted core numbers during prostate biopsy. The search included both retrospective and prospective studies, prioritizing those with substantial sample sizes and employing terms such as “prostate biopsy”, “mpMRI”, “core number”, and “cancer detection”. Key findings and limitations: Two biopsy cores identified csPCa in 55–65% of cases. This detection rate improved to approximately 90% when the number of cores was ≥5. The inclusion of perilesional and systematic biopsies could maximize the detection of csPCa (from 10% to 45%), especially in patients under active surveillance or with prior negative biopsy results, although there is an increase in the overdiagnosis of indolent tumors (from 4% to 20%). Transperineal software-assisted target prostate biopsy may enhance cancer detection, particularly for tumors located at the apex/anterior part of the prostate. Increasing the number of TBx cores may incrementally raise the risk of complications (by 2–14% with each added core) and result in severe pain and significant discomfort for up to 17% and 25% of TBx patients, respectively. However, the overall rate and severity of these complications remain within acceptable limits. Conclusions and clinical implications: The optimal number of cores for targeted prostate biopsies should balance minimizing sampling errors with effective cancer detection and should be tailored to each patient's unique prostate characteristics. Up to five cores per MRI target may be considered to enhance the detection of csPCa, with adjustments based on factors such as prostate and lesion volume, Prostate Imaging Reporting and Data System, biopsy techniques, complications, patient discomfort, and anxiety. Patient summary: In this report, we found that increasing the number of biopsy cores up to ≥5 improves the detection rates of significant prostate cancer significantly to around 90%. Although inclusion of nearby and systematic biopsies enhances detection, increasing the biopsy count may lead to higher risks of complications and indolent tumors. A customized biopsy approach based on multiple variables could be helpful in determining the appropriate number of targeted biopsies on a case-by-case basis.</p

Radical Prostatectomy: Sequelae in the Course of Time

Objective: Radical prostatectomy (RP) is a frequent treatment for men suffering from localized prostate cancer (PCa). Whilst offering a high chance for cure, it does not come without a significant impact on health-related quality of life. Herein we review the common adverse effects RP may have over the course of time. Methods: A collaborative narrative review was performed with the identification of the principal studies on the topic. The search was executed by a relevant term search on PubMed from 2010 to February 2021. Results: Rates of major complications in patients undergoing RP are generally low. The main adverse effects are erectile dysfunction varying from 11 to 87% and urinary incontinence varying from 0 to 87% with a peak in functional decline shortly after surgery, and dependent on definitions. Different less frequent side effects also need to be taken into account. The highest rate of recovery is seen within the first year after RP, but even long-term improvements are possible. Nevertheless, for some men these adverse effects are long lasting and different, less frequent side effects also need to be taken into account. Despite many technical advances over the last two decades no surgical approach can be clearly favored when looking at long-term outcome, as surgical volume and experience as well as individual patient characteristics are still the most influential variables. Conclusions: The frequency of erectile function and urinary continence side effects after RP, and the trajectory of recovery, need to be taken into account when counseling patients about their treatment options for prostate cancer

Biomarkers to personalize treatment with 177Lu-PSMA-617 in men with metastatic castration-resistant prostate cancer - a state of the art review

Radioligand therapy with Lutetium-177 (177Lu)-Prostate-specific membrane antigen (PSMA) has shown to prolong survival in metastatic castration resistant prostate cancer (mCRPC). One of the major challenges for clinicians in the future is to select those patients who would benefit most from this therapy to position it in the treatment landscape of mCRPC. This, in turn, will lead to the delivery of personalized therapies. In this narrative review article we summarize recent studies investigating both predictive and prognostic clinical, imaging-based, and molecular biomarkers to predict treatment response to 177Lu-PSMA-617 radioligand therapy with the aim of identifying men who should be considered for this approach. Of note, the evidence on the role of biomarkers currently relies on small retrospective trials and their validation in larger prospective cohorts is necessary before these results can be translated in the clinical practice

Multicentre evaluation of targeted and systematic biopsies using magnetic resonance and ultrasound image-fusion guided transperineal prostate biopsy in patients with a previous negative biopsy.

OBJECTIVES: To evaluate the detection rates of targeted and systematic biopsies in magnetic resonance imaging (MRI) and ultrasound (US) image-fusion transperineal prostate biopsy for patients with previous benign transrectal biopsies in two high-volume centres. PATIENTS AND METHODS: A two centre prospective outcome study of 487 patients with previous benign biopsies that underwent transperineal MRI/US fusion-guided targeted and systematic saturation biopsy from 2012 to 2015. Multiparametric MRI (mpMRI) was reported according to Prostate Imaging Reporting and Data System (PI-RADS) Version 1. Detection of Gleason score 7-10 prostate cancer on biopsy was the primary outcome. Positive (PPV) and negative (NPV) predictive values including 95% confidence intervals (95% CIs) were calculated. Detection rates of targeted and systematic biopsies were compared using McNemar's test. RESULTS: The median (interquartile range) PSA level was 9.0 (6.7-13.4) ng/mL. PI-RADS 3-5 mpMRI lesions were reported in 343 (70%) patients and Gleason score 7-10 prostate cancer was detected in 149 (31%). The PPV (95% CI) for detecting Gleason score 7-10 prostate cancer was 0.20 (±0.07) for PI-RADS 3, 0.32 (±0.09) for PI-RADS 4, and 0.70 (±0.08) for PI-RADS 5. The NPV (95% CI) of PI-RADS 1-2 was 0.92 (±0.04) for Gleason score 7-10 and 0.99 (±0.02) for Gleason score ≥4 + 3 cancer. Systematic biopsies alone found 125/138 (91%) Gleason score 7-10 cancers. In patients with suspicious lesions (PI-RADS 4-5) on mpMRI, systematic biopsies would not have detected 12/113 significant prostate cancers (11%), while targeted biopsies alone would have failed to diagnose 10/113 (9%). In equivocal lesions (PI-RADS 3), targeted biopsy alone would not have diagnosed 14/25 (56%) of Gleason score 7-10 cancers, whereas systematic biopsies alone would have missed 1/25 (4%). Combination with PSA density improved the area under the curve of PI-RADS from 0.822 to 0.846. CONCLUSION: In patients with high probability mpMRI lesions, the highest detection rates of Gleason score 7-10 cancer still required combined targeted and systematic MRI/US image-fusion; however, systematic biopsy alone may be sufficient in patients with equivocal lesions. Repeated prostate biopsies may not be needed at all for patients with a low PSA density and a negative mpMRI read by experienced radiologists.N. Hansen has received a research grant from RWTH Aachen University Hospital (Aachen, Germany). T. Barrett acknowledges support from Cancer Research UK, National Institute of Health Research Cambridge Biomedical Research Centre, Cancer Research UK and the Engineering and Physical Sciences Research Council Imaging Centre in Cambridge and Manchester and the Cambridge Experimental Cancer Medicine Centre. A. Warren acknowledges support from the National Institute for Health Research Cambridge Biomedical Research Centre UK. C. Kastner acknowledges that he has received speaker or mentorship fees from Siemens Healthcare and MedCom GmbH. The Department of Urology, Addenbrooke's Hospital, Cambridge, UK, also received sponsorship of various industry for organising Prostate MRI workshops. B. Hadaschik acknowledges support from the German Research Foundation

High Serum PD-L1 Levels Are Associated with Poor Survival in Urothelial Cancer Patients Treated with Chemotherapy and Immune Checkpoint Inhibitor Therapy

SIMPLE SUMMARY: Advanced urothelial bladder cancer (BC) shows a heterogeneous response to both platinum and immune checkpoint inhibitor (ICI) therapies. The PD-1/PD-L1 signaling pathway represents an immune escape mechanism and tissue PD-L1 expression was shown to be associated with patients’ prognosis and therapy response in various solid tumors. In the present study, we found for the first time that higher pretreatment serum PD-L1 levels are associated with shorter survival in platinum- and ICI-treated BC patients. ABSTRACT: Serum PD-L1 (sPD-L1) levels are associated with prognosis in various tumors but has not yet been investigated in advanced bladder cancer. We assessed pretreatment serum samples from 83 BC patients who received platinum chemotherapy and from 12 patients who underwent immune checkpoint inhibitor (ICI) therapy. In addition, on-treatment samples from further therapy cycles were collected during chemotherapy (n = 58) and ICI therapy (n = 11). Serum PD-L1 levels were determined using ELISA. High baseline sPD-L1 levels were associated with worse ECOG status (p = 0.007) and shorter overall survival for both chemotherapy- and ICI-treated patients (p = 0.002 and p = 0.040, respectively). Multivariate analysis revealed high baseline sPD-L1 level as an independent predictor of poor survival for platinum-treated patients (p = 0.002). A correlation analysis between serum concentrations of PD-L1 and matrix metalloprotease-7 (MMP-7)—a protease which was recently found to cleave PD-L1—revealed a positive correlation (p = 0.001). No significant sPD-L1 changes were detected during chemotherapy, while in contrast we found a strong, 25-fold increase in sPD-L1 levels during atezolizumab treatment. In conclusion, our work demonstrates that pretreatment sPD-L1 levels are associated with a poor prognosis of BC patients undergoing platinum and ICI therapy. Future research should prospectively address the value of sPD-L1 in predicting treatment response

Unilateral Pelvic Lymph Node Dissection in Prostate Cancer Patients Diagnosed in the Era of Magnetic Resonance Imaging-targeted Biopsy: A Study That Challenges the Dogma

PURPOSE Bilateral extended pelvic lymph node dissection at the time of radical prostatectomy is the current standard of care if pelvic lymph node dissection is indicated; often, however, pelvic lymph node dissection is performed in pN0 disease. With the more accurate staging achieved with magnetic resonance imaging-targeted biopsies for prostate cancer diagnosis, the indication for bilateral extended pelvic lymph node dissection may be revised. We aimed to assess the feasibility of unilateral extended pelvic lymph node dissection in the era of modern prostate cancer imaging. MATERIALS AND METHODS We analyzed a multi-institutional data set of men with cN0 disease diagnosed by magnetic resonance imaging-targeted biopsy who underwent prostatectomy and bilateral extended pelvic lymph node dissection. The outcome of the study was lymph node invasion contralateral to the prostatic lobe with worse disease features, ie, dominant lobe. Logistic regression to predict lymph node invasion contralateral to the dominant lobe was generated and internally validated. RESULTS Overall, data from 2,253 patients were considered. Lymph node invasion was documented in 302 (13%) patients; 83 (4%) patients had lymph node invasion contralateral to the dominant prostatic lobe. A model including prostate-specific antigen, maximum diameter of the index lesion, seminal vesicle invasion on magnetic resonance imaging, International Society of Urological Pathology grade in the nondominant side, and percentage of positive cores in the nondominant side achieved an area under the curve of 84% after internal validation. With a cutoff of contralateral lymph node invasion of 1%, 602 (27%) contralateral pelvic lymph node dissections would be omitted with only 1 (1.2%) lymph node invasion missed. CONCLUSIONS Pelvic lymph node dissection could be omitted contralateral to the prostate lobe with worse disease features in selected patients. We propose a model that can help avoid contralateral pelvic lymph node dissection in almost one-third of cases

Unilateral Pelvic Lymph Node Dissection in Prostate Cancer Patients Diagnosed in the Era of Magnetic Resonance Imaging-targeted Biopsy: A Study That Challenges the Dogma

PURPOSE: Bilateral extended pelvic lymph node dissection at the time of radical prostatectomy is the current standard of care if pelvic lymph node dissection is indicated; often, however, pelvic lymph node dissection is performed in pN0 disease. With the more accurate staging achieved with magnetic resonance imaging-targeted biopsies for prostate cancer diagnosis, the indication for bilateral extended pelvic lymph node dissection may be revised. We aimed to assess the feasibility of unilateral extended pelvic lymph node dissection in the era of modern prostate cancer imaging. MATERIALS AND METHODS: We analyzed a multi-institutional data set of men with cN0 disease diagnosed by magnetic resonance imaging-targeted biopsy who underwent prostatectomy and bilateral extended pelvic lymph node dissection. The outcome of the study was lymph node invasion contralateral to the prostatic lobe with worse disease features, ie, dominant lobe. Logistic regression to predict lymph node invasion contralateral to the dominant lobe was generated and internally validated. RESULTS: Overall, data from 2,253 patients were considered. Lymph node invasion was documented in 302 (13%) patients; 83 (4%) patients had lymph node invasion contralateral to the dominant prostatic lobe. A model including prostate-specific antigen, maximum diameter of the index lesion, seminal vesicle invasion on magnetic resonance imaging, International Society of Urological Pathology grade in the nondominant side, and percentage of positive cores in the nondominant side achieved an area under the curve of 84% after internal validation. With a cutoff of contralateral lymph node invasion of 1%, 602 (27%) contralateral pelvic lymph node dissections would be omitted with only 1 (1.2%) lymph node invasion missed. CONCLUSIONS: Pelvic lymph node dissection could be omitted contralateral to the prostate lobe with worse disease features in selected patients. We propose a model that can help avoid contralateral pelvic lymph node dissection in almost one-third of cases